JPH0418090A - Production of bisazolylpyrimidine derivative - Google Patents

Abstract

PURPOSE:To easily and safely obtain the subject compound having high transparency and purity in a short time in high efficiency while suppressing the formation of by-products by reacting a pyrimidine derivative with an azole derivative in the presence of a specific phase-transfer catalyst in an organic solvent. CONSTITUTION:The objective compound of formula III can be produced by reacting a pyrimidine derivative of formula I (one of X and Y is N and the other is CH; Z is H or methyl) (preferably bischloropyrimidine) with an azole derivative (preferably pyrazole, imidazole or 1,2,4-triazole) in the presence of a phase-transfer catalyst of formula II (R1 to R4 are alkyl, aralkyl or N- containing heterocyclic group; A<-> is anion) (preferably quaternary ammonium salt such as tetra-n-butyl-ammonium bromide) in an organic solvent preferably at 50-80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing a bisazolylpyrimidine derivative using a pyrimidine derivative as a starting material.

(Prior Art) Bisazolylpyrimidine derivatives are compounds that have been recognized for their usefulness as anti-ulcer drugs with low toxicity and cytoprotective effects.

Conventionally, as a method for producing bisazolylpyrimidine derivatives, an azole derivative (e.g., imidazole, pyrazole, triazole) and an alkali metal hydride are reacted to form an alkali salt of the azole derivative, and then the alkali salt and 2 .4-dichloropyrimidine, or 4,
Method for producing bisazolylpyrimidine derivatives by reaction with 6-dichloropyrimidine (Japanese Patent Application Laid-Open No. 63-3987
No. 5) etc. were proposed.

(Problems to be Solved by the Invention) However, in the production method using the above-mentioned conventional technology, the target substance (bisazolylpyrimidine derivative) can be obtained with a yield of 70 to 85%, but on the other hand, expensive hydrogenation is required in the production process. In addition to the use of alkali metals, a series of chemical reactions using organic solvents, reagents, and nitrogen gas must be conducted under anhydrous conditions, and highly flammable hydrogen gas is generated during the manufacturing process. Disadvantages in terms of safety have been pointed out for some time due to the manufacturing method.

Moreover, according to a follow-up experiment of the manufacturing method of the prior art,
Since a significant amount of hydrolyzed monohydroxypyrimidine is produced as a by-product during the manufacturing process, it is difficult to obtain the desired bisazolylpyrimidine derivative with high purity and high yield. That is, an attempt to increase the purity of the target bisazolylpyrimidine derivative resulted in a decrease in yield, and therefore, industrial production of the bisazolylpyrimidine derivative was not economically viable.

Under these circumstances, there has been a real need in the industry for a production method that allows bisazolylpyrimidine derivatives to be obtained easily, efficiently, and safely in a short period of time.

(Means for Solving the Problems) As a result of intensive research to improve the drawbacks pointed out in the above-mentioned prior art, the present inventors have discovered that a pyrimidine derivative and an azole derivative are reacted in the presence of a phase transfer catalyst. The present invention has been completed by discovering that bisazolylpyrimidine derivatives can be produced efficiently and with high purity by the following steps: One Y is N, the other is CH, and Z is a hydrogen atom or a methyl group.] A pyrimidine derivative represented by the formula [■] and an azole derivative are represented by the chemical formula [■]: ! (3 [wherein, R1, R2, R3, and R4 are alkyl groups,
is an aralkyl group or a heterocycle with a nitrogen atom, and A
A chemical formula [■] characterized in that the reaction is carried out in the presence of a phase transfer catalyst represented by [O is an anion]: N /) S-X 3M8 [m] (wherein χ and Y are one of N and the other is CH, Z is a hydrogen atom or a methyl group, and S is an azolyl group).

Examples of the pyrimidine derivative (1) include 2,4-dichloropyrimidine, 4,6-dichloropyrimidine, and 2,4-dichloropyrimidine.
Examples include dichloro-6-methylpyrimidine.

On the other hand, examples of azole derivatives include pyrazole, imidazole, and 1,2,4-triazole. The molar ratio of this azole derivative to the pyrimidine derivative CI) is in the range from 2.0 to 3.0, in particular from 2.0 to 2.
．． Approximately equimolar amounts of 2 are preferred.

Furthermore, suitable phase transfer catalysts (Il) are so-called quaternary ammonium salts, such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, phenyltriethylammonium chloride, tetra-n-butylammonium bromide, tetra- These include n-butylammonium, tetra-n-butylammonium hydrogen sulfate, tetraethylammonium bromide, tetraethylammonium chloride, trioctylammonium chloride, cetylpyridinium chloride, and laurylpyridinium chloride. Among these, tetra-n-butylammonium bromide and tetra-n-butylammonium hydrogen sulfate are preferred catalysts for use in the production method of the present invention.

The amount of the catalyst used is 1 for the pyrimidine derivative CI).
-20 mol%, preferably 1-5 mol%
It is.

The reaction mode of the present invention refers to a liquid-liquid or solid-liquid two-phase system reaction, and water contained in a completely non-aqueous system or a catalyst, reagent, and solvent is acceptable. It is also an acceptable form to add water.

The organic solvent used in this reaction is an aromatic hydrocarbon such as benzene, toluene, xylene, etc., or an aprotic polar solvent such as acetonitrile, dioxane, chloroform, ether, acetone, methyl ethyl ketone, dimethylformamide F. , tetrahydrofuran, etc. are preferred, and benzene, methyl ethyl ketone, and acetonitrile are particularly preferred. The amount of solvent is preferably 5 to 1,000 times the amount of the pyrimidine derivative.

The reaction temperature is between room temperature and reflux temperature, especially 50 to reflux temperature.
The temperature is preferably 80°C, and the reaction time varies depending on the reaction temperature and the catalyst used, but 1 to 10 hours is sufficient.

The following examples will explain the method for producing bisazolylpyrimidine derivatives of the present invention and the setting of optimal reaction conditions for the production method of the present invention, but the present invention should be construed as being limited to these examples. It's not a thing.

(Example) A%J+ 1: 4,6L-dipyrazulylpyrimidine 1.5ρ to 4,6-dichloropyrimidine 10
0.0g (0.67mo+) and pyrazole 113.9
g (1,675 mol) at room temperature, and to this solution was added 93.8 g (1,675 mol) of potassium hydroxide, and then 21.6 g (0 mol) of tetra-n-butylammonium bromide.
,067 mol) and stirred at 50°C for 6 hours. 500 ml of water was added to the resulting reaction solution and washed twice.

After drying the benzene layer over anhydrous sodium sulfate and concentrating the solvent under reduced pressure, the resulting residue was treated with activated carbon in acetone and then recrystallized from ethanol, giving the following analytical values 4.
,6-dipyrazolylpyrimidine 130; 6g (0,61
6 mol) was obtained.

Yield of white powder crystals (yield 91.9%) NMR (CDC1x), δ: 8.80 (IH, d, J=1.0Hz), 8.60
(2H, dd, J=2.711z, 0.7Hz)
, 8.49 (IH, d, J=1.0Hz), 7.8
2 (2H, dd, J=0.711z), 6.52
(2)! , dd, J=2.7H2), elemental analysis:
Calculated value (%) as C, oH, N6 (212, 21)
: C, 56,60; H, 3,80; N, 39.
60 analysis straight (%): C, 56,67; H, 3,76; N,
39.89M5 (m/z): 212 (
M').

145 (M” Ci N3 N2 ) B branch: 134-137 °C ゞ°7111: 4,6-dipyrazolylpyrimidine Sodium hydride (containing 60% in mineral oil) under nitrogen atmosphere 16
1 g (4.02 mol) of dry tetrahydrofuran (
Pyrazole 2 was added to a solution suspended in 200Il+ 1).
Dry tetrahydrofuran (500 ml) in which 28 g (3.35 mol) of 4,6-dichloropyrimidine was dissolved was added dropwise over 1 hour, and the reaction was allowed to proceed for 2 hours under water cooling. ) was added dropwise over 1 hour under water cooling, and the mixture was reacted overnight at about 70°C.

After the reaction mixture was distilled off under reduced pressure and the resulting residue was dissolved in dichloromethane, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform and adsorbed on silica gel. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol and decolorized using activated carbon for two times each.
By repeating the line, 135.0 g (0,646 mof yield: 47.8%) of 4,6 dipyrazolylpyrimidine was obtained.

As shown in Comparative Example 1 above, 4,6-
In the method for producing dipyrazurylpyrimidine, pyrazole and sodium hydride are mixed in dry tetrahydrofuran to synthesize the sodium salt of pyrazole, and to this, dry tetrahydrofuran of bischloropyrimidine is gradually added dropwise.
It is necessary to heat and reflux for an even longer time.

In addition, the reaction solution, which had turned dark brown, was extracted with dichloromethane after removing the tetrahydrofuran under reduced pressure, and then decolorized and recrystallized several times in order to clarify the reaction solution and improve its purity. It is necessary to repeat the process.

As described above, in the conventional method, the yield of bisazolylpyrimidine derivatives is extremely poor compared to the production method of the present invention, and
Because each process takes a long time (and requires repeated operations), it was difficult to apply this manufacturing method to a production line.

-12: ・Heavy damage caused by heavy substances at Suru Pass 4,6-
In the production process of dipyrazolylpyrimidine, the influence of the type of solvent used on the yield of bisazolylpyrimidine derivatives was investigated by high performance chromatography (HPLC column: μm BONDASP-) IERE 5 p C18,
The investigation was conducted using a flow rate of 0-5 ml/min and a mobile phase of a mixture of methanol and water (70:30).

Reaction solution 1 at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 10 hours after the start of the reaction at room temperature
0 μl was diluted 100 times with a mobile phase solvent, 2 μl of it was injected into an HP LC column, and the production ratio (%
) was calculated.

As a pyrimidine derivative, 4.6-diku00pyrimidine2. OOg (0,013
4mol)・Pyrazole 2.2h (0,
0335 mol)・TBAB (tetra-n-butylammonium bromide)0 as a phase transfer catalyst
．． 43 g (0,0013 mol) ・KOH2, 21 g (0,0335 mol) ・Solvent 40 ml ■Kazume Mata The test results of the 4,6-dipyrazolylpyrimidine production effect of each solvent are shown in Table 1 below.

As is clear from the above test results, when acetonitrile is used as a solvent, 4,6-dipyrazolylpyrimidine is rapidly produced, indicating that acetonitrile is a suitable solvent for the production method of the present invention. did.

4. In the production process of 6-dipyrazolylpyrimidine, the influence of the type of phase transfer catalyst used on the yield of bisazolylpyrimidine derivatives was investigated by high performance chromatography (HPLC column: μm BONDASPHERE 5
u C18, flow rate: 0.5 ml/min, mobile phase:
The results were investigated using a mixture of methanol and water (70:30).

Toyoko Futatsukata Same as Example 2.

As a pyrimidine derivative, 2.00 g of 4,6-dichloropyrimidine (0,013
4mol)・Pyrazole 2.28g (
0,0335 mol)・Phase transfer catalyst 0.0013 mol-K OH2,21g (0,0
335 mo+) Benzene 40 ml as a solvent Test results of the 4,6-dipyrazolylbyrimidine production effect of various phase transfer catalysts are shown in Table 2 below.

Note) #l: Tetra n-butylammonium bromide +12
: Tetra-n-butylammonium hydrogen sulfate #3: Tetra-n-butylammonium chloride 14: Tetra-n-hexylammonium bromide From the above test results, tetra-n-butylammonium bromide is superior to the other three. , very efficiently target substance 4
, 6-dibyrazolylbyrimidine was produced, indicating that this catalyst is suitable for the production method of the present invention.

4. In the production process of 6-dipyrazolylpyrimidine, the influence of various reaction temperature conditions on the yield of bisazolylpyrimidine derivatives was investigated using high performance chromatography (HP
LC Power Ram Two-BONOA-SPHERE 5 u
C18, flow rate: 0.5 ml/min, mobile phase: a mixture of methanol and water (70:30)).

core top door ri 2 Same as Example 2.

■As a Toni-pyrimidine derivative, 4.6-dichloropyrimidine 2. OOg(0,013
4mol)・Pyrazole 2, 28g
(0,0335mol)・As a phase transfer catalyst, TBA8 (tetra-n-butylammonium bromide)2
．． 28g (0,OO13mo+) ・K OH2,21g (0,0335mol) ・Benzene as solvent 40ml It was shown to.

From the test results below, if the reaction temperature is set around 80°C and the reaction is carried out, the target substance is 4.6-dipyrazolylpyrimidine derivative (4,6-dipyrazolylpyrimidine) described in Example 1. A similar substance was prepared according to the following procedure.

Organic? In 50 mI of acetonitrile, 2.4-
Dichloropyrimidine (0,05mo+) of dichloropyrimidine, 4,6-dichloropyrimidine, or 2,4-dichloro-6-methylpyrimidine and azo of pyrazole, imidazole, or 1,2,4-triazole Potassium hydroxide (0.12 mol) was dissolved at room temperature, and then tetra-n-butylammonium bromide (0.024 mol) as a phase transfer catalyst was added. Stir for hours. The resulting reaction solution was dried under reduced pressure, and the resulting residue was washed twice by adding 200 ml of benzene and 500 ml of water, and then washed twice with 300 ml of saturated brine.
Washed twice. After drying the benzene layer over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure and the resulting residue was mixed with ethanol and water (
When recrystallized from the mixed solution (1:1 volume ratio), the following 81-class bisazolylpyrimidine derivative corresponding to the reactant was obtained.

That is, by sequentially combining three types of dichloropyrimidines and three types of azoles, the following eight types of bisazolylpyrimidine derivatives other than 4,6-dipyrazolylpyrimidine described in Example 1 were produced according to the above operating procedure. It is.

(1) 4.6-diimidazolylpyrimidine 4.
6-dichloropyrimidine imidazole raw 8 polyester pale yellow powder crystals (yield 72%) NMR (DMSO-d6), δ: 8.99 (IH, d, J=1.0Hz), 8.72
(2H, d, J=1.0Hz), 8.21 (II
L d, J=1.0)lz), 8.09 (2H, d
, J=0.7Hz), 7.22 (211,d, J
=1.0IIz), planning analysis: C6゜H-IIN6(2
12,21), calculated values (%): C, 56,60; H, 3,80; N, 39.
60 analysis value (%): C, 56,62; H,'3.89; N,
39.49M5 (m/z): 212 (M'
).

(2) Morphology and yield of 4,6-di(L2,4-)riazulyl)pyrimidine/4,6-dichloropyrimidine/1,2,4-)lyazole product Pale yellow needle crystals (yield 75%) ) Σ琶R(DMSO-d6), δ: 9.56 (211,s), 9.15 (ltl, d, J=1.0tlz), 8
．． 44 (2H, s), 8.12 (LH, d, J=1.0) 1z), Motoki distribution: Ca H6N8 (214,18), calculated value (%): C, 44,86; H, 2, 82, N, 52.32
Analysis value (%): C, 44,56; H, 2,95; N, 52.
49M5 (m/z): 214 (M゛) + several points: 222-223℃ (3) 2.4-dipyrazolylpyrimidine 2,4
- Dichloropyrimidine pyrazole raw material; colorless needle crystals (yield 93%) NMR (DMSO-d,), δ: 8.87 (3H, m), 7.97 (III, d, J=1.0tlz), 7
．． 89 (LH, d, J=1.0Hz), 7.80
(ill, d, J=2.7Hz), 6.70 (L
H, d, J=1.0Hz), (i, 62 (III,
d, J=1.0Ilz), element 1 analysis: C, 6H, N
, (212,21), calculated value (%): C, 56,60; H, 3,80; N, 39.
60 Analysis value (%): C, 56,59; H, 3,77; N, 39.
32M5 (m/z): 212 (M”).

Scattered points: 147-148℃ (4) 2.4-diimidazolylpyrimidine 2,
Pale red powder crystals (yield 88%) of 4-dichloropyrimidine imidazole raw J NMR (DMSO-d6), δ: 8.90 (2H, m), 8.74 (LH, s ), 8.19 (IH,s), 8.07 (IIL s), 7.81 (III, d, J=1.0IIz), 7
．． 20 (1tL s), 7.14 (LH,s), Brother Q: C+oHe N& (212,21), calculated value (%): C, 56,60; H, 3,80; N, 39
．． 60 Analysis value (%): C, 56,71; H, 3,85; N, 39.
45M5 (m/z): 212 (M”).

Temperature: 138-140 °C 2,4-dichloropyrimidine L2,4-triazole raw knee and yield...Colorless powder crystals (yield 71%) NMR (DMSO-d6), δ: 9.78 (III, s), 9.74 (11(,s), 9.09 (11(,d, J=1.0Hz), 8.4
5 (IH, s), 8.35 (IH, s), 7.90 (18, d, J=1.011z), as Calculated value (%): C, 44,86; H, 2,82: N, 52.
32 analysis value (%): C, 44,86; I(+'2.83; N,
51.69M5 (m/z): 214 (M
).

Scattered points: 270-271 "C 02,4-dichloro-6-methylpyrimidine pyrazole Form and aggregation in living organisms Colorless needle crystals (yield 95%) NMR (DMSO-d6), δ: 8 .84 (2H, m), 7.95 (LH, s), 7.86 (III, s), 7.71 (IH, s), 6.68 (18, m), 6.60 (IH, m), 2.60 (3tl, s), Calculated value (%) as: C,, H,.N & (226,23): C, 58,40; H, 4,46; N , 37.
15 Analysis value (%): C, 58,54; H, 4,35; N, 36.
62M5 (m/z): 226 (M”
) + ore: 115-118 ℃ ・ 2,4-dichloro-6-methylpyrimidine imidazole multipotency ; ・ colorless powder crystal (yield 89%) NMR (DMSO-d6), δ: 8.83 (IH,S), 8.71 (IH,s), 8.15 (Ill, S), 8.04 (ltl, s), 7.74 (18,s), 7.19 (LH,s) , 7.13 (18,S), 2.57 (3H,s), 1 minute tJ? :C,,H,oN6 (226,23), calculated value (%): C, 58,40; H, 4,46; N+ 37.
15 Analysis value (%): C, 58,48; H, 4,47; N, 37.
13M5 (m/z): 226 (M”).

Temperature point: 183-184℃ (8) 2.4-di(1,2,4-)riazolyl -
6-methoxypyrimidine-chloropyrimidine biazole drug, 2,4-
Dichloro-6-methylpyrimidine/L2,4-triazole raw t and ratio pale yellow powder crystals (yield 74%) NMR (DMSO-d6), δ: 9.74 (ltl, s), 9.70 (IL s), 8.42 (IH, s), 8.32 (IFI, s), 7.81 (01, s), 2.67 (3)1. s), 云↑ rise: Cq He No (228,21), calculated value (%): C, 47,36; H, 3,53; N, 49.
10 Analysis value (%): C, 47,55; H, 3,54; N, 49.
08M5 (m/z): 228 (M”).

Point n: 220-223°C (Effect) In the production method of the present invention, a pyrimidine derivative and an azole derivative are mixed in a suitable solvent, and a caustic alkali (e.g., KO) and a phase transfer catalyst are added thereto. The reaction is rapidly initiated and completed within several hours at room temperature.

Note that shortening of the reaction time can be easily achieved by considering and selecting the solvent, reaction temperature, phase transfer catalyst, etc.

In addition, the production of by-products (monohydroxypyrimidine derivatives) is drastically reduced compared to conventional methods, the reaction solution is clear and yellow, and the yield and purity of the target substance, the bisazolylpyrimidine derivative, are significantly improved. .

Furthermore, the present invention is preferable from the viewpoint of manufacturing cost. For example, if benzene is used as the solvent, pyrimidine derivatives, azole derivatives, and by-products (monohydroxypyrimidine derivatives) can also be washed away by adding water for washing to the reaction vessel after the reaction is complete, and thoroughly washing with water while stirring. This also brings about the advantage in the purification process that a high purity bisazolylpyrimidine derivative, which is the target substance, can be obtained from the residue obtained by distilling off benzene under reduced pressure.

That is, the present invention provides a method for producing bisazolylpyrimidine derivatives that exhibits excellent actions and effects, such that bisazolylpyrimidine derivatives can be obtained efficiently, safely, and simply in a short time. be.

Claims (11)

[Claims] (1) Chemical formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, one of X and Y is N and the other is CH, and Z is a hydrogen atom or a methyl group.] The represented pyrimidine derivative and azole derivative are represented by the chemical formula [II]: ▲There are numerical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R_1, R_2, R_3, and R_4 are an alkyl group, an aralkyl group, or a heterocycle with a nitrogen atom, and A^■ is an anion] Chemical formula [III] characterized in that the reaction is carried out in an organic solvent in the presence of a phase transfer catalyst represented by: ▲ Numerical formula, chemical formula, There are tables, etc. ▼ [III] Bisazolyl represented by [In the formula, one of X and Y is N and the other is CH, Z is a hydrogen atom or a methyl group, and S is an azolyl group] A method for producing a pyrimidine derivative. (2) The method for producing a bisazolylpyrimidine derivative according to claim 1, wherein the organic solvent is either an aromatic hydrocarbon or an aprotic polar solvent. (3) Claim 2, wherein the aromatic hydrocarbon is benzene.
A method for producing a bisazolylpyrimidine derivative as described in . (4) The aprotic polar solvent is acetonitrile,
The method for producing a bisazolylpyrimidine derivative according to claim 2, which is either methyl ethyl ketone or tetrahydrofuran. (5) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 4, wherein the pyrimidine derivative is bischloropyrimidine. (6) The bischloropyrimidine is 2,4-dichloropyrimidine, 4,6-dichloropyrimidine, or
, 4-dichloro-6-methylpyrimidine, the method for producing a bisazolylpyrimidine derivative according to claim 5. (7) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 6, wherein the azole derivative is any one of pyrazole, imidazole, or 1,2,4-triazole. (8) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 7, wherein the phase transfer catalyst is a quaternary ammonium salt. (9) The quaternary ammonium salt is any one of tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium chloride, or tetra-n-hexylammonium bromide. A method for producing a bisazolylpyrimidine derivative according to claim 8. (10) The bisazolylpyrimidine derivative is 4,6
-dipyrazolylpyrimidine, 4,6-diimidazolylpyrimidine, 4,6-di(1,2,4-triazolyl)pyrimidine, 2,4-dipyrazolylpyrimidine, 2,4-
Diimidazolylpyrimidine, 2,4-di(1,2,4-
triazolyl)pyrimidine, 2,4-dipyrazolyl-6
-Methylpyrimidine, 2,4-diimidazolyl-6-methylpyrimidine, or 2,4-di(1,2,4-triazolyl)-6-methylpyrimidine, according to any one of claims 1 to 9. A method for producing the bisazolylpyrimidine derivative described. (11) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 10, wherein the reaction is carried out at a reaction temperature of 50°C to 80°C.